Research Spotlight

Packer, M. (2019). “Are healthcare systems now ready to adopt sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in chronic heart failure? The culmination of a 20-year journey.” Eur Heart J May 23. [Epub ahead of print].

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Do the effects of neprilysin inhibition on high-sensitivity troponin T and soluble ST2 advance our management of heart failure? It is always gratifying to see biomarkers change in a favourable direction, but such changes do not reliably identify the true mechanism of drug action or quantify the magnitude of the clinical benefits. Furthermore, there are no data to support the use of (or changes in) these biomarkers as a decision tool to select patients for treatment or to determine the appropriate dose for long-term therapy. As one of the two principal investigators of the PARADIGM-HF trial, I was dismayed when obstacles were placed in the path of physicians who sought to prescribe neprilysin inhibition to patients with chronic heart failure. As a matter of personal choice, I have had no financial relationship with the manufacturer of sacubitril/valsartan (Novartis) since the publication of the primary papers, and I have not been involved in any efforts to market or give sponsored presentations on behalf of the drug. However, at the same time, I have been an ardent supporter of the findings of the trial, which represented my second chance (after the disappointment of the OVERTURE trial) to finally demonstrate that neprilysin inhibitors can meaningfully potentiate the survival benefits of conventional antagonists of the renin–angiotensin system in patients with heart failure. If the PIONEER-HF trial allows all cardiologists to embrace that conclusion, I am very pleased. If the biomarker data published in this issue are motivating to practitioners to increase their appropriate prescribing of sacubitril/valsartan, I am delighted to hear that. If physicians, healthcare systems, and the manufacturer are prepared to work collaboratively to facilitate affordable unrestricted access to a life-saving treatment for heart failure, I doubt that patients will complain. (Excerpt from text of this editorial, p. 3; no abstract available.)

Noe, M. H., M. T. Wan, D. B. Shin, A. W. Armstrong, K. C. Duffin, Z. C. Chiesa Fuxench, R. E. Kalb, A. Menter, E. L. Simpson, J. Takeshita, S. K. Tyring, A. S. Van Voorhees, N. N. Mehta and J. M. Gelfand (2019). “Patient-Reported Outcomes of Adalimumab, Phototherapy, and Placebo in the Vascular Inflammation in Psoriasis Trial: A Randomized Controlled Study.” J Am Acad Dermatol Jun 1. [Epub ahead of print].

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BACKGROUND: There is limited data about the impact of narrowband ultraviolet B phototherapy on patient-reported measures of health-related quality of life (HRQoL). OBJECTIVE: To evaluate the impact of adalimumab and phototherapy on HRQoL. METHODS: We examined patient-reported outcomes (PROs) from a multicenter, randomized placebo-controlled trial (NCT01553058). Dermatology Life Quality Index (DLQI) and EQ-5D-3L were evaluated every 4 weeks. RESULTS: We enrolled 97 patients: 30.9% female, mean (SD) age 43.5(14.0) years, median (interquartile range) PASI 16.7(13.9-21.6). At week 12, patients being treated with adalimumab (OR: 2.88, 95% CI:1.02, 8.17) and phototherapy (OR: 8.83, 95% CI:2.47, 31.57) were more likely to achieve the minimal clinically important difference (MCID) in DLQI compared to placebo. There were higher odds of achieving the MCID for the EQ-5D-3L Index score when comparing phototherapy versus placebo (OR: 9.78, 95% CI:2.99, 31.95) and phototherapy versus adalimumab (OR: 4.07, 95% CI:1.42, 11.70). LIMITATIONS: small sample size, secondary analysis, generalizability CONCLUSION: Phototherapy and adalimumab both improve skin-related quality of life and overall health related quality of life compared to placebo in patients with psoriasis, however, phototherapy treated patients achieved more improvement in overall health quality of life compared to patients treated with adalimumab.

Navas, M. C., S. Glaser, H. Dhruv, S. Celinski, G. Alpini and F. Meng (2019). “Hepatitis C Virus Infection and Cholangiocarcinoma: An Insight into Epidemiologic Evidences and Hypothetical Mechanisms of Oncogenesis.” Am J Pathol 189(6): 1122-1132.

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Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial-mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.

Mehta, R. S., S. G. Holtan, T. Wang, M. T. Hemmer, S. R. Spellman, M. Arora, D. R. Couriel, A. M. Alousi, J. Pidala, H. Abdel-Azim, I. Ahmed, M. Aljurf, M. Askar. . . J. A. Yared and D. J. Weisdorf (2019). “GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.” Blood Adv 3(9): 1441-1449.

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We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

McCullough, P. A., H. S. Mehta, D. P. Cork, C. M. Barker, C. Gunnarsson, S. Mollenkopf, J. Van Houten and P. Verta (2019). “The healthcare burden of disease progression in Medicare patients with functional mitral regurgitation.” J Med Econ May 20. [Epub ahead of print].

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OBJECTIVE: This retrospective database analysis estimated the incremental effect that disease progression from non-clinically significant functional mitral regurgitation (nsFMR) to clinically significant FMR (sFMR) has on clinical outcomes and costs. METHODS: We examined Medicare Fee for Service beneficiaries with nsFMR, defined as those with a heart failure diagnosis prior to MR. Patients were classified as ischemic if there was history of: CAD, AMI, PCI, or CABG. The primary outcome was time to sFMR, defined as pulmonary hypertension, atrial fibrillation, mitral valve surgery, serial echocardiography, or death, using a Cox hazard regression model. Annualized hospitalizations, inpatient hospital days, and healthcare expenditures were also modeled. RESULTS: Patients with IHD had higher risk (Hazard Ratio: 1.22 [1.14, 1.30]) for disease progression compared to patients without. The progression cohort had significantly more annual inpatient hospitalizations (non-IHD, 1.32; IHD, 1.40) than the non-progression cohort (non-IHD, 0.36; IHD, 0.34) and significantly more annual inpatient hospital days (non-IHD, 13.07; IHD, 13.52) than the non-progression cohort (non-IHD, 2.29; with IHD, 2.08). The progression cohort had over 3.5 times higher costs versus the non-progression cohort, independent of IHD (non-IHD, $12,798 versus $46,784; IHD, $12,582 versus $49,348). CONCLUSION: Treating FMR patients earlier in their clinical trajectory may prevent disease progression and reduce high rates of healthcare utilization and expenditures.